Mechanisms of Ultrasound Neuromodulation Effects in Diabetes
Study Details
Study Description
Brief Summary
This study aims to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Drop-outs will be replaced; data will be used as much as can be. Subjects will undergo a Screening visit to assess eligibility and will then be scheduled to undergo 2 outpatient US treatment visits.
On day three subjects first undergo a third ultrasound session and then will either undergo Oral Glucose Tolerance Test (OGTT) with carbon13 (13C-glucose) tracer administration and subsequent NMR spectroscopy OR if enrolled into the HEC study arm will undergo euglycemic clamp testing. Following these procedures there will be an approximately two-week follow-up observational Period (with CGM). A two-week washout period will be followed by another cycle of the same procedures of either OGTT/NMR or HEC study, respectively.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1: Ultrasound during a hyperinsulinemic euglycemic clamp (HEC). Hepatic ultrasound during a hyperinsulinemic euglycemic clamp (HEC). |
Device: Ultrasound
The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.
Diagnostic Test: CGM glucose reading
A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.
Diagnostic Test: HEC - Hyperinsulinemic-Euglycemic-Clamp
A constant i.v. insulin and variable glucose infusion will be used to determine insulin sensitivity of study participants.
|
| Experimental: Cohort 2: Ultrasound then NMR with unlabeled glucose. Hepatic ultrasound and subsequent NMR measurement of glycogen with unlabeled glucose. |
Device: Ultrasound
The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.
Diagnostic Test: OGTT with unlabeled glucose and liver NMR
Subjects will undergo an OGTT with unlabeled glucose to measure liver glycogen concentration by NMR spectroscopy.
Diagnostic Test: CGM glucose reading
A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.
|
| Experimental: Cohort 3: Ultrasound then NMR with carbon13 labeled glucose. Hepatic ultrasound and subsequent NMR measurement of glycogen with carbon13 labeled glucose. |
Device: Ultrasound
The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.
Diagnostic Test: OGTT with carbon-13 labeled glucose and liver NMR
Subjects will undergo an OGTT with carbon-13 labeled glucose to measure liver glycogen synthesis rate by NMR spectroscopy.
Diagnostic Test: CGM glucose reading
A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.
|
| Experimental: Cohort 4: Dual site ultrasound stimulation followed by CGM glucose recording alone. Hepatoportal plexus + superior mesenteric plexus dual site ultrasound stimulation followed by CGM glucose recording alone. |
Device: Ultrasound
The General Electric LOGIQ E10 ultrasound pulsed doppler imaging system and C1-6-D XDclear abdominal curvilinear probe will be used to administer ultrasound.
Diagnostic Test: CGM glucose reading
A continuous glucose monitor (CGM) will be collecting glucose level changes over a 10-14day time period after the ultrasound.
|
Outcome Measures
Primary Outcome Measures
- Insulin Sensitivity [Measured during HE clamp.]
Insulin Sensitivity calculated as Glucose disposal rate / insulin ratio during steady state (M/I) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)
- Glucose disposal rate [Measured during HE clamp.]
Glucose disposal rate during steady state (M) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)
- Glucose metabolic clearance rate [Measured during HE clamp.]
Glucose metabolic clearance rate during steady state (MCR) to evaluate the effect of hepatic ultrasound treatment on changes from baseline in whole-body insulin sensitivity during a hyperinsulinemic, euglycemic clamp (HE Clamp)
Secondary Outcome Measures
- Absolute glycogen level [during glucose tolerance testing (for 180 minutes).]
The effect of hepatic plexus-directed pFUS on absolute glycogen level by observing the metabolic fate of unlabeled glucose ingested during oral glucose tolerance testing measured by 13C liver NMR-spectroscopy.
- Glycogen synthesis rates [during glucose tolerance testing (for 180 minutes).]
Glycogen synthesis rates are derived from plasma 13C -glucose levels achieved during the OGTT and subsequent appearance of 13C -tracer in liver glycogen
- Change from baseline in blood glucose (BG) time spent in defined glucose ranges [1 week]
Change from baseline in blood glucose (BG) time spent in defined glucose ranges assessed using a continuous glucose monitoring system (CGMS)
- Average daily glucose [1 week]
Average daily glucose assessed using a continuous glucose monitoring system (CGMS)
- Low blood glucose index (LBGI) [1 week]
Frequency of low glucose events detected during continuous glucose measurement.
- High blood glucose index (HBGI) [1 week]
Frequency of high glucose events detected during continuous glucose measurement.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Type 2 diabetic (T2D) subjects must be aged 18-80 and must be able to provide written informed consent
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All subjects must have had T2D for at least 3 months prior to study enrollment. All subjects must be either on diet and exercise or oral antidiabetic agents alone, not on insulin or any form of insulin or GLP-1 receptor agonists.
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Subjects must demonstrate:
- A past medical history of abnormal glucose control and carry a diagnosis of T2D according to current ADA criteria:
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A fasting plasma glucose (FPG) level of 126 mg/dL (7.0 mmol/L) or higher, or
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A 2-hour plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher during a 75-g oral glucose tolerance test (OGTT), or
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A random plasma glucose of 200 mg/dL (11.1 mmol/L) or higher in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis or
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A hemoglobin A1c (HbA1c) level of 6.5% or higher.
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Be willing to carry a continuous glucose monitor for at least 10 days.
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Be willing to follow all required instructions by study personnel and appear for the required laboratory assessments, including euglycemic clamps and OGTT.
Exclusion Criteria:
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BMI >40kg/m2.
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Untreated proliferative retinopathy
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Creatinine clearance < 60 ml/min/1.73 m2.
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Serum creatinine ≥1.5 mg/dL
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Positive pregnancy test, or presently breast-feeding, or failure to follow effective contraceptive measures
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Active infection including hepatitis C, hepatitis B, HIV,
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Any history of Active alcohol abuse
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History of non-adherence to prescribed regimens
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Baseline Hgb < 10.5 g/dL in females, or < 13 g/dL in males
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History of coagulopathy or medical condition requiring long-term anticoagulant therapy (low-dose aspirin treatment is allowed)
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Co-existing cardiac disease with active medication titration. Patients on stable meds without active cardiac complications permitted.
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Liver function tests outside of 3xUL of normal range
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GI disorders potentially interfering with the ability to absorb oral medications and h/o upper GI surgery that might have changed anatomy in the target areas.
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Any medical condition or medication that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Yale School of Medicine | New Haven | Connecticut | United States | 06520 |
Sponsors and Collaborators
- Yale University
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Raimund Herzog, MD, MHS, Yale University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2000034954
- 1R01DK131127-01A1